Abstract
Interferon regulatory factor 3 (IRF3) is important for innate antiviral responses; accordingly, many viruses target and inactivate IRF3. The ability of the Herpes simplex virus type 1 (HSV-1) immediate early protein ICP0 to inhibit IRF3 is controversial and has not been studied solely in the context of a wild type HSV-1 infection. Discrepancies in the literature surround the mechanism by which ICP0 antagonizes the IRF3 pathway, the cellular localization of ICP0 inhibitory activity and the ability of ICP0 to interfere with interferon and interferon-stimulated gene induction. In this study, we set out to investigate the role of ICP0 localization and the requirement of the proteasome during the inhibition of IRF3 activation within the context of an HSV-1 infection. Collectively, the results presented herein demonstrate that incoming wild type HSV-1 activates IRF3 and that de novo produced ICP0 prevents sustained IRF3 activation following its translocation from the nucleus to the cytoplasm. While previous studies implicate the E3 ubiquitin ligase domain of ICP0 in mediating its biological functions, including the inhibition of IRF3, we show that cytoplasmic ICP0 does not require the proteasome for this activity. Instead, proteasome function is required to localize ICP0 to the cytoplasm where it mediates its inhibitory effect independent of E3 ubiquitin ligase activity. The importance of these findings is discussed within the context of an HSV-1 infection.
Highlights
Interferon (IFN) regulatory factor 3 (IRF3) is a constitutively expressed transcription factor that controls the expression of IFN and IFN-stimulated genes (ISGs) following virus recognition
To correlate Interferon regulatory factor 3 (IRF3) activation with a functional antiviral response, induction of ISG56 was examined by western blot analysis, as this protein is induced rapidly and efficiently during an IRF3-dependent antiviral response [12,43]
We examine the requirement of ICP0 localization during the inhibition of Sendai virus (SeV)- or polycytidylic acid (polyI):C-mediated IRF3 activation using the ICP0 mutant viruses, R7914 and D8
Summary
Interferon (IFN) regulatory factor 3 (IRF3) is a constitutively expressed transcription factor that controls the expression of IFN and IFN-stimulated genes (ISGs) following virus recognition. All identified innate immune receptors are capable of signaling through IRF3 to mediate their antiviral effects, including toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors and DNA sensors such as DAI [1,2]. There are several avenues the host defense machinery can employ to activate IRF3-mediated antiviral responses. The activation of IRF3 has been intensively studied and is reviewed in detail elsewhere [7,8,9]. IRF3 is degraded via the ubiquitin-proteasome pathway [10,11]. The critical nature of IRF3 was shown in studies where its absence results in abrogation of innate antiviral responses [4,12,13]. Diverse viruses encode proteins that inhibit IRF3 activation [14]
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